Richard Lehman’s journal review—13 July 2015

richard_lehmanNEJM 9 July 2015 Vol 373
111 First they defined a new disease category. Then they promoted a mechanistic explanation. Then they made everyone focus on the pathway that matched the latest drugs. Then they made billions of dollars selling the drugs. By the time the whole edifice started to look shaky, everybody was complicit and nobody wanted to admit they had been fooling themselves and their patients. Just think of any condition that interests you. Does this ring true? Alas, it almost certainly will, wherever you look. Take the kind of chronic lung deterioration which is labelled Chronic Obstructive Pulmonary Disease. A lot of the disease isn’t actually obstructive, but we’ve been led to believe that it necessarily involves accelerated deterioration of pulmonary function which is best tracked by measuring the forced expiratory volume in 1 second (FEV1). A group of investigators, funded by an unrestricted grant from GlaxoSmithKline, decided to see if this is what actually happened in three cohorts of adults who had their FEV1 measured over a number of decades. And lo! half of them started off with a low FEV1 in early adulthood and then showed a subsequent mean decline in FEV1 which was no faster than normal, despite the same smoking exposure as those who showed accelerated decline. So there are two fundamentally different subclasses of COPD, which probably need fundamentally different approaches to management. And I bet if you look in most areas of medicine, you’ll find the same gross ignorance about natural history.

123 You have advanced squamous-cell non–small-cell lung cancer (NSCLC) and have disease progression during or after first-line chemotherapy. So you are going to die quite soon and you want your last months to be bearable. Bristol-Myers Squibb has produced a monoclonal antibody, nivolumab, that might help you live a bit longer. The alternative is docetaxel. At one year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. So far so good. But “treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group.” That’s amazingly better! For once I’m in the odd position of telling a pharma company that their paper undersells their product: this key advantage doesn’t appear in the conclusion of the abstract.

136 Oh dear, this is not leukin good. I am going have to take you down interleukin pathways that I don’t understand, because I suspect that nobody quite understands them. And now a further warning: this may drive you mab. We are talking of guselkumab versus adalimumab, and I shall throw in secukinumab for good measure. These antibodies are used to treat plaque psoriasis. And this trial shows that guselkumab, a new anti–interleukin-23 monoclonal antibody, beats adalimumab, a now fairly venerable antibody against tumour necrosis factor-α, judged by a clinical score for psoriasis clearance. But although I know little about psoriasis and find it hard to tell one mab from another, I can’t help but remember that another psoriasis treatment is secukinumab, which targets member A from the cytokine family of interleukin 17. Obviously we need a new head-on trial between guselkumab and secukinumab, but how do these interleukin pathways intersect? I will leave you to judge:

“The proinflammatory interleukin-12–mediated type 1 helper T (Th1) cell and interleukin-23–mediated type 17 helper T (Th17) cell signaling pathways are up-regulated in psoriatic lesions; antibodies that inhibit both interleukin-12 and interleukin-23 and those that inhibit interleukin-17 inhibit the expression of molecular and clinical disease characteristics associated with psoriasis. Interleukin-12 induces the development of Th1 cells, whereas interleukin-23 is required for terminal differentiation of Th17 cells and maintenance of the Th17 phenotype. Th17 cells produce interleukin-17 and interleukin-22, both of which have proinflammatory effects in skin that are relevant to the pathogenesis of psoriasis.” Splendid. N.B. Both these interleukin antibodies lead to an increase in infections and gusel up a lot of dollars.

JAMA 7 July 2015 Vol 314
25 I do wish this viewpoint piece on The Role of Physicians in the Era of Predictive Analytics was not behind a paywall. The last year has seen overheated proponents of risk-lowering treatment with statins roaring with moral indignation at those who fail to share their view about what the population should do to reduce “its” risk. But there is a fundamental category error here, which this superb brief article sets out to explain. “What does a 10% risk of an event within the next decade mean to the individual for whom it was generated? Contrary to what is thought, this risk level is not that person’s personal risk because probability is not meaningful in an individual context. However, if a risk function accurately predicts the number of events for a group of 10 individuals at a 10% risk, on average, one person will experience an event. The question then becomes were all 10 individuals equally likely to experience this event? The answer matters because only if this is the case will individual risk be equal to group risk.” Frame that and put it on your office wall, in case you are visited by some epidemiologist or public health enthusiast.

31 It’s this very issue of risk that makes shared decision making so difficult. And people (doctors as well as patients) vary enormously in how they understand this conundrum and in the weight they give to particular outcomes. Say you have had an unprovoked pulmonary embolism. For some hours you felt breathless and thought you would die. The last thing you want is ever to have another. Or perhaps you were with your mother when she had a major cerebral haemorrhage. The last thing you want is to have the same happen to you. It’s now 6 months from your PE. Do you stay on warfarin or don’t you? This French trial shows that if you keep taking it you stand a 1.6% chance of having recurrent VTE in the next 18 months, whereas if you don’t, your risk is 13.4%. But on warfarin your chance of a major bleed is 2.2% while it is just 0.5% if you stop taking it. Now work out how you might discuss these options in real life. (I’ve just checked the small print of the paper and in fact none of the major bleeds was cerebral. And of course not all PEs are equal. So this narrative is misleading – which in itself is instructive. It shows how well you need to know the evidence in order to do proper SDM: otherwise a lot of it will be confabulation).

JAMA Intern Med July 2015
OL Most of the authors of this breast cancer study are not medics. They don’t need to be, because what they have been looking at is a mixture of statistics and logic. If screening mammography is effective, then it will have the effect of reducing the number of larger tumours detected over time (because they will be picked up at the less than 2cm stage), and it will reduce mortality from breast cancer in proportion to the amount of screening done. But: “When analyzed at the county level, the clearest result of mammography screening is the diagnosis of additional small cancers. Furthermore, there is no concomitant decline in the detection of larger cancers, which might explain the absence of any significant difference in the overall rate of death from the disease. Together, these findings suggest widespread overdiagnosis.” This is a huge, painstaking study of 16 million women 40 years or older who resided in 547 counties, of whom 53 207 were diagnosed with breast cancer. A classic of the Less is More literature.

OL Why do clinicians so rarely read or value qualitative research? Are we scared of thinking about the way we do medicine? Why don’t we all get involved in big observational studies of how people actually respond to what we do to them? This study about sharing of information in later life uses the second-best option of inviting patients and carers to discussion groups. Even so a number of important themes emerge (read the abstract if you can’t access the full article), the last of which is, as always, that “no ‘one-size-fits-all’ approach can satisfy individuals’ different preferences.”

Lancet 11 July 2015 Vol 386
OL Most of the articles in this week’s paper Lancet are ones I’ve mentioned when they appeared on-line, so I spent some time instead looking at this head-to-head trial of two drugs for post-menopausal osteoporosis. It was funded by Amgen, Lilly, and the US National Institutes of Health. It begins by declaring that a large number of post-menopausal women have this “disease.” And, “although the therapeutic options in osteoporosis treatment have expanded greatly in the past two decades, no currently approved therapy is able to restore skeletal integrity in most patients with established disease.” Now if you believe that increasing bone density is the most important factor in preventing osteoporotic fractures, then this is quite a useful trial. Sadly for Lilly, the makers of teriparatide, it is a clear win for the competitor drug. “In postmenopausal osteoporotic women switching from teriparatide to denosumab, bone mineral density continued to increase, whereas switching from denosumab to teriparatide results in progressive or transient bone loss.” Amgen will be delighted, because this 94 person trial (which it didn’t even have to pay the full cost of) could result in millions of women being given denosumab for the rest of their lives. But do we know what denosumab does to women if given long term? Not really. And osteoporosis is not a disease, but a risk factor for fractures, which are not diseases either, but events, albeit sometimes catastrophic ones.

BMJ 11 July 2015 Vol 351
Kevin Barraclough’s editorial on the new NICE guidelines for cancer referral is a wonder of deep and gently subversive analysis. “One concern is that I will retire from general practice and spend the rest of my remaining years in hospital outpatient clinics.” Oh no Kevin, retire as soon as you can, never visit a doctor and write as much as you can. The book on quantum physics is so near to completion (this is not a joke—this was Kevin’s first degree subject and he has drafted most of the chapters) and then we must have one on how to do wise medicine.

Symptom sorters have been around for centuries, if not millennia. But in the last 15 years they have become almost ridiculously important, especially in the triage of out-of-hours calls in the NHS. Before I finished doing emergency primary care a few months ago, I began to wonder what would come in next as an urgent booking. A hairy mole? An unusual fart? But I must not get too Chaucerian about these instruments. In this study of 23 free online symptom checkers, they were found to provide a correct diagnosis in one third of evaluations and suggested appropriate triage in about half.

I’ve previously commented about a number of register-based studies which try to establish which, if any, SSRI antidepressants might be associated with birth defects. Here is the latest, which uses Bayesian analysis to combine results from previously published analyses with data from a US multicentre population based case-control study of birth defects. The upshot is that sertraline and citalopram seem to be quite safe, whereas paroxetine and fluoxetine are likely to carry an increased (but still tiny) risk for a limited range of anomalies.

Person centred coordinated care: where does the QOF point us?” In the opposite direction is the simple answer, of course. Ergo, the sooner the QOF system is binned, the better it will be for patients and for primary care. Writing from within the NHS Medical Directorate, Martin McShane comes amazingly close to saying this in so many words. “We need to initiate a debate on how to move away from paying for the capture of process data, which should be a normal part of good clinical care, and we need to create a new transparent system of incentives that will support primary care, the NHS, and the wider health and care economies to deliver person centred coordinated care.”

Plant of the Week: Geranium “Ann Folkard”

This exuberant cranesbill geranium (G procurrens x G psilostemon) trails into neighbouring plants and bears flowers of startling magenta with black eyes. It’s cheap and easy to grow and you need to have at least one to add flair and beauty to your summer garden. Buy five.